Osteoporosis is the most common form of metabolic bone disease. Although it may occur secondary to a number of underlying diseases, 90% of all cases appear to be idiopathic. Postmenopausal women are particularly at risk to idiopathic osteoporosis ("postmenopausal osteoporosis"). Another high risk group for idiopathic osteoporosis are the elderly of either sex ("senile osteoporosis").
In the various forms of osteoporosis, bone fractures, which are the result of bone loss that has reached the point of mechanical failure, frequently occur. Postmenopausal osteoporosis is characterized by fractures of the wrist and spine. Femoral fractures seem to be the dominant feature of senile osteoporosis.
The mechanism by which bone is lost in osteoporotics is believed to involve an imbalance in the process by which the skeleton renews itself. This process has been termed bone remodeling. It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells) which then refill with new bone the cavity left by the osteoclasts.
In a healthy adult subject, the rate at which osteoclasts and osteoblasts are formed is such that bone formation and bone resorption are in balance. However, in osteoporotics an imbalance in the bone remodeling process develops which results in bone being lost at a rate faster than it is being made. Although this imbalance occurs to some extent in most individuals as they age, it is much more severe and occurs at a younger age in osteoporotics.
There have been many attempts to treat osteoporosis with a variety of pharmacologic agents with the goal being to either slow further bone loss or, more desirably, to produce a net gain in bone mass. It appears as though there are agents available, such as estrogen, which will slow further bone loss in osteoporotics, but agents or methods of treatment which will result in the replacement of bone which has already been lost have been very elusive.
The ability of polyphosphonates to inhibit bone loss has been well documented in animals and man. However, these compounds have, thus far, not proven to be particularly useful in diseases such as osteoporosis where there is chronic loss of bone, and therefore a perceived need for chronic treatment. The reason for this probably lies in the tight coupling between the bone resorption and formation in the human skeleton. When one attempts to chronically manipulate one phase of the skeletal remodeling cycle (bone resorption or formation), a similar effect occurs in the opposing process and any change produced in then negated. In the case of polyphosphonates, chronic inhibition of bone resorption tends to produce chronic inhibition of bone formation. Furthermore, long term chronic inhibition of remodeling is not desirable since it appears that this may lead to the development of spontaneous bone fractures.
It has now been discovered that bone loss can be inhibited and bone mass can be increased if certain polyphosphonates are given, in a limited amount, according to a specific regimen of intermittent, rather than chronic, dosing. This regimen forms the heart of the present invention. This treatment apparently uncouples bone resorption and formation by selectively inhibiting the resorption phase of bone remodeling without appreciably affecting the formation phase, and thus producing the net increase in skeletal mass.
It is therefore an object of the present invention to provide a method for treating or preventing osteoporosis which does not require prolonged administration of pharmacologic agents, and which does not result in a significant inhibition of bone formation.
A further object of the present invention is to provide a kit to facilitate the necessary strict compliance with the method of treatment of the present invention.
U.S. Pat. No. 3,683,080, to Francis (issued Aug. 8, 1972), discloses pharmaceutical compositions containing polyphosphonate compounds. These compositions are useful for inhibiting deposition and mobilization of calcium phosphates in animal tissue. This patent also discloses a method for treating or preventing conditions involving pathological calcification and hard tissue demineralization, such as osteoporosis, in animals by utilizing the chronic dosing of these compositions.
U.S. Pat. No. 4,230,700, to Francis (issued Oct. 28, 1980), discloses the conjoint administration of certain polyphosphonate compounds, in particular diphosphonates, and vitamin D-like anti-rachitic compounds for inhibition of the anomalous mobilization of calcium phosphate in animal tissue. See also U.S. Pat. No. 4,330,537, to Francis (issued May 18, 1982). The patents specify that the administration of the phosphonate and the vitamin D-like compounds be conjoint.
Siris et al., Arthritis and Rheumatism, 23 (10), 1177-1184 (1980), discloses research into intermittent therapy for Paget's disease involving high doses of EHDP or long periods of treatment with EHDP.
Rasmussen et al., "Effect of Combined Therapy with Phosphonate and Calcitonin on Bone Volume in Osteoporosis", Metabolic Bone Disease and Related Research, 2, 107, (1980), discloses a treatment regimen consisting of continuous administration of inorganic phosphate and intermittent administration of calcitonin.
Anderson et al., Calcified Tissue International, 36, 341-343 (1984), discloses a sequential and intermittent method of treating osteoporosis based on the ADFR theory of bone treatment which requires a period during which a bone activation compound, such as inorganic phosphate, is administered to the patient, to be followed by a period during which a bone resorption repressing compound, such as ethane-1-hydroxy-1,1-diphosphonic acid, is administered, followed by a period free of medication to allow the bone to be built up.